Pharmacological inhibition of cyclin-dependent kinases has emerged as a possible treatment option for various cancer types. We recently identified substituted imidazo[1,2-c]pyrimidin-5(6H)-ones as inhibitors of cyclin-dependent kinase 2 (CDK2). Here, we report the synthesis of derivatives modified at positions 2, 3, 6 or 8 prepared using Suzuki-Miyaura cross-coupling, halogenation, Dimroth-type rearrangement and alkylation as the main synthetic methods. The compounds displayed micro- to submicromolar inhibition of CDK2/cyclin E activity. Binding of the most potent compound 3b to CDK2 was determined using isothermal titration calorimetry. The co-crystal structure of 3b in complex with fully active CDK2 was solved, revealing the binding mode of 3b in the ATP pocket and a hydrogen bonding interaction with hinge region residue Leu83. Evaluation against leukaemia cell lines revealed low cytotoxicity, which is in line with the high selectivity towards CDK2. This study demonstrates that substituted imidazo[1,2-c]pyrimidines can be exploited for future kinase inhibitor development.

细胞周期蛋白依赖性激酶的药理学抑制作用已成为多种癌症的可能治疗选择。我们最近确定了取代的咪唑并[1,2 - c ]嘧啶-5（6 H）-ones作为细胞周期蛋白依赖性激酶2（CDK2）的抑制剂。在这里，我们报道了使用铃木宫浦交叉偶联，卤化，Dimroth型重排和烷基化作为主要合成方法制备的，在2、3、6或8位修饰的衍生物的合成。这些化合物显示出对CDK2 / cyclin E活性的微摩尔至亚微摩尔抑制作用。用等温滴定热法测定最有效的化合物3b与CDK2的结合。3b的共晶体结构解决了与具有完全活性的CDK2的复合物中的Aβ ，揭示了3b在ATP口袋中的结合模式以及与铰链区残基Leu83的氢键相互作用。对白血病细胞系的评估显示出低细胞毒性，这与对CDK2的高选择性相符。这项研究表明，取代的咪唑并[1,2- c ]嘧啶可用于未来激酶抑制剂的开发。